Parkinson's disease (PD) is a common and highly debilitating movement disorder caused by the degeneration of dopaminergic neurons in the midbrain. The molecular mechanisms responsible for PD pathogenesis are poorly understood, and there are currently no preventative treatments for this disorder. Epidemiological studies aimed at the identification of environmental factors that influence the incidence of PD have provided overwhelming data in support of a substantially reduced risk of PD among coffee and tobacco users. While there are several possible interpretations of these findings, we hypothesize that tobacco and coffee contain chemicals that confer neuroprotection. To test this hypothesis we have been using two different Drosophila models of PD. Specifically, the two PD models that we have been using in our work include a fly strain bearing a null allele of the parkin gene, and a transgenic fly strain overexpressing the human 1-synuclein protein. Both of our fly models exhibit multiple characteristics of PD, most notably, selective degeneration of dopaminergic neurons in the central nervous system. In preliminary studies we have used our fly PD models to test the neuroprotective potential of tobacco and coffee extracts and to compare the neuroprotective effects of these extracts to nicotine and caffeine, the suspected neuroprotective agents of tobacco and coffee, respectively. Our studies indicate that coffee and tobacco are indeed neuroprotective in both of our fly models. However, nicotine and caffeine alone do not appear to confer neuroprotection, suggesting that the neuroprotective components of tobacco and coffee are novel chemical species. There are two major aims of the current application: the first aim involves identification and structural characterization of the neuroprotective components of tobacco and coffee; the second aim involves experiments to define the mechanism by which tobacco and coffee confer neuroprotection. Drosophila is ideal for these studies because the short generation time, powerful genetic tools, and evolutionary conservation of neurodegenerative disease mechanisms in this organism will allow us to quickly and efficiently explore the potential of these neuroprotective agents in a fashion that should be pertinent to humans. Our studies could ultimately lead to the development of preventative treatment strategies for PD. PUBLIC HEALTH RELEVANCE: People who smoke or drink coffee develop Parkinson's disease (PD) at a significantly lower frequency than the general public. These findings lead us to hypothesize that tobacco and coffee contain chemicals that confer protection from developing PD. We will use two different fly models of PD to test this hypothesis and to identify the specific chemical agents in tobacco and coffee that are responsible for protection. Our studies could ultimately lead to the development of preventative treatment strategies for PD. [unreadable] [unreadable]